This MYH7 Gly741Trp variant has been reported in both sporadic and familial HCM cases (Arai S, et al., 1995; Perrot A, et al., 2005). Parents of sporadic HCM cases were not clinically or genetically affected, and the variant was shown to segregate with disease in affected family members (Arai S, et al., 1995). Interestingly, a variant at the same position resulting in a different amino acid change, Gly741Arg, has extensively been described and attributed to sporadic and familial HCM (Fananapazir L, et al., 1993; Richard P, et al., 2003; Van Driest SL, et al., 2004; Song L, et al., 2005; Kaski JP, et al., 2009; Marsiglia JD, et al., 2013). The MYH7 Gly741Trp variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), and the 1000 genomes project (http://www.1000genomes.org/). We have identified this variant in one HCM family with familial disease - both affected individuals carry the variant. In summary, we classify this variant as "pathogenic" based on the available literature, segregation data, absence in controls, and de novo occurrence.

Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position

The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID: 8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>C p.Gly741Arg - Variation ID 14098). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PP1_Moderate; PP3

The G741W variant in the MYH7 gene has been previously reported in multiple individuals diagnosed with HCM. In at least two families, the G741W variant was present in all affected relatives available for testing, and was absent from 192 control alleles (Arai S et al., 1995; Perrot A et al., 2005). The G741W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While G741W results in a conservative substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is class conserved in evolution. Moreover, in silico analysis predicts G741W is probably damaging to the protein structure/function. Furthermore, mutations at the same residue (G741A, G741R) as well as mutations in nearby residues (A742E, E743D) have also been reported in association with HCM, further supporting the functional importance of this residue and region of the protein. In summary, Gly741Trp in the MYH7 gene is interpreted as a disease-causing variant.

This sequence change replaces glycine with tryptophan at codon 741 of the MYH7 protein (p.Gly741Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate withÂ¬â€ hypertrophic cardiomyopathy (HCM)Â¬â€ in a family (PMID: 8533830) and also has been observed in multiple individuals with HCM (PMID: 15856146, 22112859,Â¬â€ 22429680,Â¬â€ 25935763,Â¬â€ 26914223, 27532257).Â¬â€ ClinVar contains an entry for this variant (Variation ID: 177665). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The p.Gly741 amino acid residue in MYH7 has been determined to be clinically significant (Invitae). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

The Gly741Trp variant in MYH7 has been reported in at least 3 individuals with HCM (Arai 1995, Perrot 2005, Pan 2012) and segregated with disease in 4 affected relatives from 2 families. This variant has also been previously identified by our laboratory in 5 individuals with HCM. It was absent from large population studies. Glycine (Gly) at position 741 is conserved in mammals, though not across evolutionarily distant species (birds and fish). The change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, another variant at this position (Gly741Arg) is reported to be disease-causing. In summary, although additional studies are required to fully establish its clinical significance, the Gly741Trp variant is likely pathogenic.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Gly741Trp (c.2221G>T) The variant has been seen in at least 9 unrelated individuals with HCM with moderately segregation data in one family. Arai et al (1995) reported a Japanese family with four individuals who all had HCM and carried p.Gly741Trp. The authors of that paper refer to an additional Japanese case, reported in a book chapter by Kimura et al (1994). Perrot et al (2005) reported two siblings from a German family who both had HCM and this variant. Santos et al (2012) observed the variant in one of 80 Portuguese patients with HCM. Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). It is not currently listed in ClinVar (as of October 3rd 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and mutationtaster predicts it to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Arg (Van Driest et al 2004, we consider this variant very likely disease causing), p.Gly741Ala (primary data unavailable). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that another variant at this codon, p.Gly741Arg, confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6896 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 1 Oct 2014). The variant is listed in dbSNP (rs121913632), however the only submissions are OMIM and LMM (as of 1 October 2014). The variant is not listed in the 1000 genomes dataset (as of 1 October 2014). The variant was not observed in the following published control samples: 96 (Perrot et al 2005), 100 (Santos et al 2012), 200 (Bos et al 2014).

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